Synthesis, pharmacological evaluation, and mechanistic study of adefovir mixed phosphonate derivatives bearing cholic acid and l-amino acid moieties for the treatment of HBV

Bioorg Med Chem. 2019 Aug 15;27(16):3707-3721. doi: 10.1016/j.bmc.2019.07.012.

Tao Li ¹, Jing Li ¹, Yang Yang ¹, Yilin Han ¹, Dirong Wu ¹, Tao Xiao ¹, Yang Wang ¹, Ting Liu ², Yonglong Zhao ¹, Yongjun Li ³, Zeqin Dai ⁴, Xiaozhong Fu ⁵

Affiliations

1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Pharmacy, Guizhou Medical University, Guiyang 550004, PR China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, PR China.
2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Pharmacy, Guizhou Medical University, Guiyang 550004, PR China; Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, PR China.
3 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, PR China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, PR China.
4 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Pharmacy, Guizhou Medical University, Guiyang 550004, PR China.
5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, Guizhou, PR China; School of Pharmacy, Guizhou Medical University, Guiyang 550004, PR China; National Engineering Research Center of Miao's Medicines & Engineering Research Center for the Development and Application of Ethnic Medicine and TCM, Ministry of Education, Guiyang 550004, Guizhou, PR China. Electronic address: xiaozhong_fu@sina.com.

PMID: 31301948 DOI: 10.1016/j.bmc.2019.07.012

Abstract

The deficiency of nucleos(t)ide analogues (NAs) as anti-hepatitis B virus (HBV) drugs in clinical use is attributable to their insufficient enrichment in liver and non-target organ toxicity. We aimed to develop potent anti-HBV adefovir derivatives with hepatotrophic properties and reduced nephrotoxicity. A series of adefovir mono l-amino acids, mono cholic acid-drug conjugates were designed and synthesized, and their Antiviral activity and uptake in rat primary hepatocytes and Na⁺-dependent taurocholate co-transporting polypeptide (NTCP)-HEK293 cells were evaluated. We isolated compound 6c as the optimal molecular candidate, with the highest Antiviral activity (EC₅₀ 0.42 μmol/L, SI 1063.07) and highest cellular uptake in primary hepatocytes and NTCP-HEK293 cells. In-depth mechanistic studies demonstrated that 6c exhibited a lower toxicity in HK-2 cells when compared to adefovir dipivoxil (ADV). This is because 6c cannot be transported by the human renal organic anion transporter 1 (hOAT1). Furthermore, pharmacokinetic characterization and tissue distribution of 6c indicates it has favorable druggability and pharmacokinetic properties. Further docking studies suggested compounds with ursodeoxycholic acid and l-amino acid groups are better at binding to NTCP due to their hydrophilic properties, indicating that 6c is a potential candidate as an anti-HBV therapy and therefore merits further investigation.

Keywords

Adefovir; Hepatitis B virus; Hepatotrophic properties; Nephrotoxicity; Organic anion transporter 1.

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